Structural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3
Changyao Li,
Youwei Xu,
Wenxin Su,
Xinheng He,
Jingru Li,
Xinzhu Li,
H. Eric Xu,
Wanchao Yin
Affiliations
Changyao Li
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Lingang Laboratory, Shanghai 200031, China
Youwei Xu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Wenxin Su
Guangzhou University of Chinese Medicine, Zhongshan Institute for Drug Discovery, Guangdong 510000, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong 528400, China
Xinheng He
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
Jingru Li
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
Xinzhu Li
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
H. Eric Xu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Lingang Laboratory, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Corresponding author
Wanchao Yin
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong 528400, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Guangzhou University of Chinese Medicine, Zhongshan Institute for Drug Discovery, Guangdong 510000, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding author
Summary: Bombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled receptor that regulates energy homeostasis and insulin secretion. As a member of the bombesin receptor (BnR) family, the lack of known endogenous ligands and high-resolution structure has hindered the understanding of BRS3 signaling and function. We present two cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with the heterotrimeric Gq protein in its active states: one bound to the pan-BnR agonist BA1 and the other bound to the synthetic BRS3-specific agonist MK-5046. These structures reveal the architecture of the orthosteric ligand pocket underpinning molecular recognition and provide insights into the structural basis for BRS3’s selectivity and low affinity for bombesin peptides. Examination of conserved micro-switches suggests a shared activation mechanism among BnRs. Our findings shed light on BRS3’s ligand selectivity and signaling mechanisms, paving the way for exploring its therapeutic potential for diabetes, obesity, and related metabolic disorders.
